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Non‐small cell lung cancer (NSCLC) is highly correlated with smoking and has very low survival rates. Multiple studies have shown that stem‐like cells contribute to the genesis and progression of NSCLC. Our results show that the transcriptional coactivator yes‐associated protein 1 (YAP1), which is the oncogenic component of the Hippo signaling pathway, is elevated in the stem‐like cells from NSCLC and contributes to their self‐renewal and ability to form angiogenic tubules. Inhibition of YAP1 by a small molecule or depletion of YAP1 by siRNAs suppressed self‐renewal and vascular mimicry of stem‐like cells. These effects of YAP1 were mediated through the embryonic stem cell transcription factor, Sox2. YAP1 could transcriptionally induce  Sox2  through a physical interaction with Oct4;  Sox2  induction occurred independent of TEAD2 transcription factor, which is the predominant mediator of YAP1 functions. The binding of Oct4 to YAP1 could be detected in cell lines as well as tumor tissues; the interaction was elevated in NSCLC samples compared to normal tissue as seen by proximity ligation assays. YAP1 bound to Oct4 through the WW domain, and a peptide corresponding to this region could disrupt the interaction. Delivery of the WW domain peptide to stem‐like cells disrupted the interaction and abrogated  Sox2  expression, self‐renewal, and vascular mimicry. Depleting YAP1 reduced the expression of multiple epithelial‐mesenchymal transition genes and prevented the growth and metastasis of tumor xenografts in mice; overexpression of Sox2 in YAP1 null cells rescued these functions. These results demonstrate a novel regulation of stem‐like functions by YAP1, through the modulation of  Sox2  expression. S tem  C ells   2015;33:1705–1718

YAP 1 Regulates OCT 4 Activity and SOX 2 Expression to Facilitate Self‐Renewal and Vascular Mimicry of Stem‐Like Cells